The objective of this application is to predict cognitive decline in adults with Down syndrome and to ultimately provide a platform for early intervention to prevent the dementia associated with Alzheimer's disease. Individuals with Down syndrome have an increased incidence of Alzheimer's disease over age 40 years. Once dementia has begun, treatments appear to have little efficacy. This study will assess whether imaging and biomarker analysis will predict cognitive decline in adults with Down syndrome prior to the onset of dementia. Cognitive decline will be assessed using a battery of informant based and direct measures which demonstrate sensitivity to changes associated with developmental aging and dementia in Down syndrome. Specific Aim 1 will determine whether quantitative EEG imaging will predict cognitive decline. When adults with Down syndrome develop seizures, the cognitive decline may become precipitous. This aim seeks to identify neurophysiological markers reflecting epilepsy and EEG disorganization as predictors of cognitive decline. Specific Aim 2 will assess whether amyloid uptake is increased in brain by positron emission tomography as a predictor of dementia. Individuals with Down syndrome have triplication of the amyloid precursor protein gene on chromosome 21. The investigators predict that amyloid uptake will increase in those individuals with Down syndrome who go on to develop cognitive decline. Specific Aim 3 will examine several biomarkers that have a high likelihood of predicting cognitive decline in DS. Based upon the evidence implicating chronic oxidative stress in Down syndrome, the investigators will focus on critical region mutations in mitochondrial DNA, with the hypothesis that their number will increase in association with cognitive decline. Additionally, they shall examine two key chemical components of Alzheimer's plaques and tangles (beta-amyloid and hyperphosporylated tau) in the cerebrospinal fluid. It is predicted that increased levels of hyperphosporylated tau and lower levels of beta-amyloid in cerebrospinal fluid will herald cognitive decline, as has been demonstrated in patients with Alzheimer's disease in the general population. This aim will also examine cerebrospinal fluid and plasma levels for inflammatory factors that have been shown to be altered in Alzheimer's disease in the general population. The investigators predict that pathological processes leading to cognitive decline in Down syndrome will trigger a characteristic signature of changes in cytokines, chemokines, and growth factors in spinal fluid and plasma. Finally, Specific Aim 4 of this study seeks to develop a predictive model by which the changes in imaging and biomarker measures will allow a composite assessment of the likelihood of cognitive decline. It is predicted that this model will form one basis for considering early intervention to prevent dementia in Down syndrome. This application is consistent with the mission of NICHD in directing attention towards the prevention of disease and disability in a population with a common developmental disorder. PROJECT NARRATIVE: This application is relevant to public health in predicting factors associated with cognitive decline and Alzheimer's disease in adults with Down syndrome. By developing a predictive model for cognitive decline, a rationale is established for early intervention to prevent or treat dementia. This project is relevant to individuals with Down syndrome and those at risk for Alzheimer's disease in the general population.